Descrizione del progetto
Affrontare i rischi di malattie cardiovascolari nei pazienti diabetici
Il diabete è associato a malattie microvascolari che interessano principalmente le arterie coronarie e le arterie periferiche. Tuttavia, le attuali terapie per il diabete non riducono gli eventi cardiovascolari. In questo contesto, il progetto RGD-Diabetes, finanziato dal CER, cercherà una soluzione. In particolare, la ricerca si concentrerà su una proteina circolante, la proteina-1 legante IGF, che possiede diverse caratteristiche favorevoli (sensibilizzazione all’insulina, miglioramento dell’intolleranza al glucosio, riduzione della pressione sanguigna, riduzione dell’arteriosclerosi e aumento della riparazione vascolare). Questi effetti sono mediati dall’interazione del dominio RGD della proteina con i recettori dell’integrina α5β1 della superficie cellulare, che aumenta l’assorbimento di glucosio stimolato dall’insulina nelle cellule muscolari scheletriche e la secrezione di insulina stimolata dal glucosio nelle isole pancreatiche. Il progetto intende verificare se l’interazione RGD-integrina possa essere sfruttata terapeuticamente nel diabete.
Obiettivo
In Europe, 58 million people are living with type 2 diabetes and 36 million people are at risk of developing the condition. Macrovascular disease is the commonest cause of morbidity and mortality in type 2 diabetes, yet current diabetes therapies have failed to consistently reduce cardiovascular events. In my Starting Grant, I discovered that a circulating protein, IGF binding protein-1, possesses several favourable characteristics– including insulin sensitisation, amelioration of glucose intolerance, blood pressure lowering, reduced atherosclerosis and increased vascular repair. These effects are mediated by interaction of the protein’s RGD-domain with cell-surface α5β1 integrin receptors, which increases insulin-stimulated glucose uptake in skeletal muscle cells and glucose-stimulated insulin secretion in pancreatic islets. Hence the ‘idea’ from my Starting Grant is that RGD-integrin interaction could be exploited therapeutically in diabetes. In this Proof-of-Concept grant, we will take the first step towards commercialisation of the idea by designing and testing small molecule mimics of the RGD domain of IGFBP1 as diabetes therapeutics. Using in silico modelling based on the known structures of IGFBP1 and the α5β1 integrin ectodomain, we will design a small molecule library of commercially available potential agonists. We will carry out virtual high throughput screening of the library for molecules matching the shape and electrostatic potential of the RGD domain of IGFBP1 as predicted to bind to α5β1 integrin. As contingency, we will also identify in silico ‘me-too’ analogues of known integrin ligands. We will test the best quality hits through ADME profiling and validate therapeutic activity in vitro and in vivo. At the end of the project, we anticipate we will have identified small molecule RGD mimics which can subsequently be progressed through the drug-discovery pipeline through translation grant funding or pharmaceutical industry Open Innovation schemes.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-POC - Proof of Concept GrantIstituzione ospitante
LS2 9JT Leeds
Regno Unito